DESCRIPTION: The proposed research combines methodology and total synthesis. The targets chosen for total synthesis are halichondrin and rhizoxin. Both natural products are relatively scarce and demonstrate potent antimitotic activity by binding to the vinca domain on tubulin. In vivo activity against vinblastine and vincristine resistant cell lines has led to the selection of rhizoxin for Phase II clinical evaluation, and halichondrin B is currently in preclinical development. As a key strategy in both syntheses, two-directional chain synthesis is being applied. Three new methods for the synthesis of polysubstituted hydropyrans are also proposed. Planned variations of the Claisen rearrangement include a tandem glycolate ester enolate Claisen/ring-closing metathesis sequence, a desymmetrization of C2-symmetric substrates via a dioxanone rearrangement, and asymmetric catalysis of the dioxanone Claisen rearrangement by cationic metal complexes. Based on the second method, a short synthesis of KDO, a membrane component of Gram-negative bacteria, is proposed.